New use of pyrimidine - or triazine - 2 carbonitiles for treating diseases associated with cysteine prostease activity and novel pyrimidine-2-carbonitile derivatives

ABSTRACT

The present invention therefore provides use of a compound of formula (I) and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases S, K, F, L and B. Of particular interest are diseases associated with Cathepsin S. In addition, this invention also discloses processes for the preparation of such inhibitors.

The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases S, K, F, L and B. Of particular interest are diseases associated with Cathepsin S. In addition this invention also discloses processes for the preparation of such inhibitors.

BACKGROUND OF THE INVENTION

Cathepsin S is a member of the papain superfamily of cysteine proteases which also encompasses Cathepsins B, H, L, O and K. Cathepsin S plays a key role in the processing of invariant chain in MHC class II complexes allowing the complex to associate with antigenic peptides. MHC class II complexes are then transported to the surface of the cell for presentation to effector cells such as T cells. The process of antigen presentation is a fundamental step in initiation of the immune response. In this respect inhibitors of cathepsin S could be useful agents in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Cathepsin S has also been implicated in a variety of other diseases involving extracellular proteolysis such as the development of emphysema in COPD through degradation of elastin and in Alzheimers disease.

Other Cathepsins notably K and L have been shown to degrade bone collagen and other bone matrix proteins. Inhibitors of these cysteine proteases would be expected to be useful in the treatment of diseases involving bone resorption such as osteoporosis.

The present invention therefore provides use of a compound of formula (I)

in which:

-   X is N or CA where A is hydrogen, halogen, CHR²R³, OR², NR²R³, SR²; -   R² and R³ are independently hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl     both of which can optionally contain one or more O, S or NR⁴ groups     where R⁴ is hydrogen or C₁₋₆ alkyl, and can be optionally     substituted by aryl, heteroaryl, NR⁵R⁶ where R⁵ and R⁶ together with     the nitrogen atom to which they are attached form a 4-7 membered     ring optionally containing a further O, S, NR⁴, or R2 and R3     together with the nitrogen atom to which they are attached form a     4-7 membered ring optionally containing a further O, S, NR⁴ group,     or R2 and R3 are aryl or heteroaryl groups, both aryl and heteroaryl     groups being optionally substituted by halogen, amino, hydroxy,     cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl,     NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆     alkoxy, NR⁷R⁸ or SR⁷ where R⁷ and R⁸ are independently hydrogen or     C₁₋₆ alkyl; -   R and R¹ are independently a group Y(CH₂)pR⁹ where p is 0, 1, 2 or 3     and Y is O or NR¹⁰ where R¹⁰ is hydrogen, C₁₋₆ alkyl or C₃₋₆     cycloalkyl; -   and R⁹ is hydrogen, C₁₋₆ alkyl which can optionally contain one or     more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl, or a 3     to 7-membered saturated ring optionally containing a carbonyl group,     one or more O, S or N atoms, or an aryl or heteroaryl group     containing one to four heteroatoms selected from O, S or N, the     saturated ring, aryl and heteroaryl groups all being optionally     substituted by halogen, amino, hydroxy, cyano, nitro, carboxy,     CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴,     ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or     NR¹¹R¹² where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or     together with the nitrogen atom to which they are attached form a 5-     or 6-membered saturated ring optionally containing a further O, S or     NR⁴ group; -   or R/R¹ is a group NR¹⁰(CHR¹⁰)CONR²R³ or NR¹⁰(CH₂)_(q)CONR²R³ where     q is 1, 2 or 3; or R/R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴     together with the nitrogen atom to which they are attached form a 4     to 7-membered saturated ring optionally containing a carbonyl group,     O, S or N atom and optionally substituted by C₁₋₆ alkyl, amino,     hydroxy, CO₂C₁₋₆ alkyl, halogen, NR⁵R⁶, NR⁷R⁸, C₁₋₆ alkylNR¹⁷R¹⁸     where R¹⁷ and R¹⁸ are independently hydrogen or C₁₋₆ alkyl,     CONR¹⁵R¹⁶ where R¹⁵ and R¹⁶ are independently hydrogen or     C₁₋₆-alkyl, or optionally substituted by aryl, phenoxy, COphenyl, or     a heteroaryl group, the latter four groups being optionally     substituted by halogen, amino, hydroxy, cyano, nitro, carboxy,     CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴,     ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or     NR¹¹R¹² where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or     together with the nitrogen atom to which they are attached form a 5-     or 6-membered saturated ring optionally containing a further O, S or     NR⁴ group;     and pharmaceutically acceptable salts or solvates thereof, in the     manufacture of a medicament for use in the inhibition of cathepsin S     in a mammal such as man.

In the context of the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched. Aryl groups include phenyl and naphthyl. Heteroaryl groups include 5- or 6-membered, 5,6- or 6,6-fused heterocyclic rings containing one or more heteroatoms selected from N, S, O. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, thiophene, quinoline, isoquinoline, benzimidazole, benzofuran, benzothiophene and indole.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.

Preferably X is CH, NHR², OR² where R² is preferably H or C₁₋₆ alkyl.

Preferably R is a group Y(CH₂)_(p)R⁷ where p is 0 or 1 and Y is NR⁸ where R⁸ is hydrogen and R⁷ is substituted phenyl. Preferably R⁷ is phenyl substituted by halogen, especially chloro. More preferably R⁷ is phenyl substituted by chloro in the 4-position.

Preferably R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form a morpholine ring, piperidine or piperazine ring optionally substituted, or R¹ is a group NR⁹R¹⁰ where R¹⁰ is H or C₁₋₆ alkyl and R⁹ is C₁₋₆ alkyl which can optionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl.

The most preferred substituents for R and R¹ are those of the examples exemplified herein.

Preferred compounds of the invention include:

-   4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile, -   4-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, -   4-(7-Azabicyclo[2.2.1]hept-7-yl)-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-piperidin-1-yl-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-(ethylamino)-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-(3-hydroxypyrrolidin-1-yl)-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-[(2-piperidin-1-ylethyl)amino]-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile, -   4-[(3-Chlorobenzyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile, -   4-Morpholin-4-yl-6-[(4-morpholin-4-ylphenyl)amino]-1,3,5-triazine-2-carbonitrile, -   4-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, -   4-Morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile, -   4-(1,4′-Bipiperidin-1′-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, -   4-[4-(1H-Imidazol-1-yl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, -   4-[4-(4-Chlorobenzoyl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, -   4-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-6-morpholinyl-1,3,5-triazine-2-carbonitrile, -   4-Morpholin-4-yl-6-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3,5-triazine-2-carbonitrile, -   1-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-diethylpiperidine-3-carboxamide, -   4-[4-(2-Methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, -   N˜2˜-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N˜1˜,N˜1˜-bis{4-[N-(4-cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N-isobutylglycyl]morpholin-3-yl}-N˜2˜-isobutylglycinamide, -   4-Morpholin-4-yl-6-[(2-pyridin-3-ylethyl)amino]-1,3,5-triazine-2-carbonitrile, -   4-{[2-(2-Furyl)ethyl]amino}-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrie, -   4[(4-Chlorophenyl)amino]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-carbonitrile, -   4-Azetidin-1-yl-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   4-[(4-Methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   4-(4-Chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-(dimethylamino)pyrimidine-2-carbonitrile, -   4-[(1-Methylpiperidin-4-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   4-(Cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile, -   4-[(6-Chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   1-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-prolinamide, -   4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]pyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidine-2-carbonitrile, -   tert-Butyl     4-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}piperazine-1-carboxylate, -   4-[(4-Chlorophenyl)amino]-6-(cyclopropylamino)pyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-piperazin-1-ylpyrimidine-2-carbonitrile, -   (2S)-N˜2˜-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-N˜1˜,N˜1˜-bis[4-(N-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-leucyl)morpholin-3-yl]-L-leucinamide, -   5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   4-[(3S)-3-Aminopyrrolidin-1-yl]-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-5-methoxypyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-5-methoxypyrimidine-2-carbonitrile, -   4-[(4-Chlorophenyl)amino]-5-methoxy-6-(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile, -   1-{6-[(4-Chlorophenyl)amino]-2-cyano-5-methoxypyrimidin-4-yl}piperidine-3-carboxamide, -   4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile, -   5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, -   5-Amino-4[(4-Chlorophenyl)amino]-6-(ethylamino)pyrimidine-2-carbonitrile,     and pharmaceutically acceptable salts thereof.

In a further aspect the invention provides a compound of formula (I) as defined above but where X is CH, NHR², OR² where R² is preferably H or C₁₋₆ alkyl. For the novel compounds of the invention other preferred groups and compounds are those defined above.

The present invention further provides a process for the preparation of a compound of formula (I) which comprises

-   (i) reaction of a compound of general formula (II) -   wherein L1, L2 and L3 represent a leaving group (e.g. halide,     sulphide, sulfoxide or sulphone group), preferably the sulphide is     oxidised to a sulphoxide or sulphone group before displacement. An     oxidising agent such as a peracid may be used, for example     meta-chloroperbenzoic acid in dichloromethane at room temperature. -   L1 and L2 may be displaced by R and R¹ respectively where R and R¹     are defined in formula (I) and L3 may be displaced by a cyanide     salt. The sequence of displacement of L1, L2 and L3 may be varied.

When X═CA and A=OR², SR² or CHR²R³ compounds of general formula (ID may be formed by treatment of compounds of general formula (III) and (IV) with phosphorous oxychloride at reflux. R¹⁹ is preferably C₁₋₆ alkyl or benzyl

-   (ii) when X═CA and A=NH₂ reaction of a compound of general     formula (V) under a hydrogen atmosphere with palladium catalyst at     room temperature.

According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent.

According to a further feature of the present invention there is provided a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof

The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man. In particular the compounds of the invention are useful in the treatment of inflammation and immune disorders such as asthma, rheumatoid arthritis, COPD, multiple sclerosis, Crohn's disease, Alzheimers and pain, such as neuropathic pain. Preferably the compounds of the invention are used to treat pain, in particular neuropathic pain.

In particular the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin S in a warm blooded animal, such as man. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 1 mgkg⁻¹ to 100 mgkg⁻¹ of the compound, preferably in the range of 5 mgkg⁻¹ to 20 mgkg⁻¹ of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X. 100 Lactose Ph.Eur. 179 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur. 229 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (c) Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur. 92 Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur. 389 Croscarmellose sodium 100 Magnesium stearate 1. (e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl e cyclodextrin may be used to aid formulation.

Note

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

The following examples illustrate the invention.

EXAMPLE 1 4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile (i) 4,6-Dichloro-N-4-chlorophenyl)-1,3,5-triazin-2-amine

4-Chloroaniline (8.28 g) was added to a mixture of trichlorotriazine (6 g) in acetone/ice-water (1:1, 60 ml) and stirred for 1 h. The solid was filtered off and dried to give a light brown solid, 8.5 g.

MS: APCI(+ve) 275/7(M+1)

(ii) 6-Chloro-N˜2˜-(4-chlorophenyl)-N˜4˜,N˜4˜-dimethyl-1,3,5-triazine-2,4-diamine

A solution of dimethylamine in tetrahydrofuran (2M, 1.1 ml) was added to a mixture of the product from step (i) (0.3 g) in acetone (10 ml) and ice-water (10 ml). After stirring for 1 h, the solid was filtered, washed with water and dried. Yield 0.3 g solid.

MS: APCI(+ve) 284(M+1)

(iii) 4-[(4-Chlorophenyl)amino]-6-dimethylamino)-1,3,5-triazine-2-carbonitrile

Sodium cyanide (0.138 g) was added to a solution of the product from step (ii) (0.4 g) in N,N-dimethylformamide (20 ml) and heated at 90° C. for 16 h. The mixture was partitioned between ethyl acetate and water, a solid formed which was filtered off and purified by RPHPLC 15-85% acetonitrile in aqueous trifluoroacetic acid. Yield 0.05 g

MS: APCI(+ve) 275(M+1)

1H NMR: (DMSO-d6) δ 10.30(1H, bs), 7.72-7.37(4H, 2×d), 3.14(6H, s)

EXAMPLE 2 4-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrile (i) 2,4-Dichloro-6-morpholin-4-yl-1,3,5-triazine

Morpholine was added dropwise to stirred solution of trichlorotriazine (6.7 g), N,N-diisopropylethylamine (60.5 ml) in dichloromethane (50 ml) at −78° C. The solid formed was filtered off, washed with water, dried to give a white solid (6.7 g).

MS: APCI(+ve) 235(M+1)

(ii) 4-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrie

4-Phenoxypiperidine (0.15 g) was added to a solution of the product from step (i) (0.2 g), N,N-diisopropylethylamine (1.47 ml) in tetrahydrofuran and stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with ether/isohexane (1:2). Yield 0.3 g white solid. The solid was dissolved in N,N-dimethylformamide (20 ml), sodium cyanide (0.1 g) added and heated at 90° C. for 32 h. The mixture was partitioned between ethyl acetate and water, the organic layer separated, washed with water, brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by RPIPLC 35-95% acetonitrile in aqueous trifluoroacetic acid. Yield 0.079 g

MS: APCI(+ve) 367(+H)

1H NMR: (DMSO-d6) δ 7.31-6.91(5H, m), 4.66(1H, m), 4.11-4.04(2H, m), 3.70-3.57(10H, m), 2.00-1.95(2H, m), 1.63-1.60(2H, m)

EXAMPLES 3-26

Examples 3-26 were prepared according to the methods of example 1 or 2 using the appropriate amines.

EXAMPLE 3 4-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 315(M−1)

1H NMR: (DMSO-d6) δ 10.41(1H, bs), 7.66-7.31(4H, 2×d), 3.74-3.64(8H, m)

EXAMPLE 4 4-(7-Azabicyclo[2.2.1]hept-7-yl)-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 325(M−1)

1H NMR: (IMSO-d6) δ 10.37(1H, bs), 7.70-7.35(4H, 2×d), 4.64-4.61(2H, m), 1.74-1.52(8H, m)

EXAMPLE 5 4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 299(M−1)

1H NMR: (DMSO-d6) δ 10.29(1H, bs), 7.75-7.36(4H, 2×d), 3.54-3.49(4H, m), 1.96-1.90(4H, m)

EXAMPLE 6 4-[(4-Chlorophenyl)amino]-6-piperidin-1-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 313(M−1)

1H NMR: (DMSO-d6) δ 10.29(1H, bs), 7.66-7.38(4H, 2×d), 3.74-3.73(4H, m), 1.64-1.55(6H, m)

EXAMPLE 7 4-[(4-Chlorophenyl)amino]-6-(ethylamino)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 273(M−1)

1H NMR: (DMSO-d6) δ 10.31(1H, bs), 8.39-7.34(5H, m), 3.36-3.27(2H, q), 1.10(3H, t)

EXAMPLE 8 4-[(4-Chlorophenyl)amino]-6-(3-hydroxypyrrolidin-1-yl)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 315(M−1)

1H NMR: (DMSO-d6) δ 10.31(1H, s), 7.76-7.38 (4H, m), 5.06(1H, m), 4.38(11H, m), 366-3.45(4H, m), 2.04-1.95(2H, m)

EXAMPLE 9 4-[(4-Chlorophenyl)amino]-6-[(2-piperidin-1-ylethyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 358(M+1)

1H NMR: (DMSO-d6) δ 10.38(1H, s), 8.35-7.34(5H, m), 3.37(2H, m), 2.43-2.34(6H, m), 1.48-1.44(6H, m)

EXAMPLE 10 4-[(4-Chlorophenyl)amino]-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 389(M−1)

1H NMR: (DMSO-d6) δ 10.33(1H, bs), 7.68-7.16(9H, m), 4.72-4.69(2H, d), 3.09-2.85(3H, m), 1.88-1.55(4H, m)

EXAMPLE 11 4-[(3-Chlorobenzyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 287(M−1)

1H NMR: (DMSO-d6) δ 8.59-8.44(1H, t), 7.37-7.22(4H, m), 4.47-4.44(2H, m), 3.07-3.03(6H, m)

EXAMPLE 12 4-Morpholin-4-yl-6-[(4-morpholin-4-ylphenyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 368(M+1)

1H NMR: (DMSO-d6) δ 10.09(1H, s), 7.57-7.48(2H, d), 6.93-6.84(2H, d), 3.72-3.55(12H, m), 3.07-3.00(4H, m)

EXAMPLE 13 4-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 339(M−1)

1H NMR: (DMSO-d6) δ 10.13(1H, s), 7.21-6.80(3H, m), 4.23-3.64(12H, m)

EXAMPLE 14 4-Morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 351(M+1)

1H NMR: (DMSO-d6) δ 7.35-7.22(5H, m), 4.67-2.64(13H, m), 1.93-1.48(4H, m)

EXAMPLE 15 4-(1,4′-Bipiperidin-1′-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 358(M+1)

1H NMR: (DMSO-d6) δ 9.23(1H, bm), 4.75-4.64(2H, m), 3.71-3.36(11H, m), 2.93-2.87(4H, m), 2.08-1.37(10H, m)

EXAMPLE 16 4-[4-(1H-Imidazol-1-yl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 341(M+1)

1H NMR: (DMSO-d6) δ 9.11(11H, s), 7.89-7.88(1H, s), 7.69-7.68(1H, s), 4.79-4.62(31H, m), 3.74-3.02(10H, m), 2.17-1.88(4H, m)

EXAMPLE 17 4-[4-(4-Chlorobenzoyl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 413(M+1)

1H NMR: (DMSO-d6) δ 8.04-8.02(2H, d), 7.64-7.60(2H, d), 4.62-4.52(2H, m), 3.80-3.69(5H, m), 3.32-3.08(61H, m), 1.87-1.43(4H, m)

EXAMPLE 18 4-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 387(M+1)

1H NMR: (DMSO-d6) δ 8.14-8.13(1H, s), 7.65-7.62(1H, d), 6.91-6.89(1H, d), 3.82-3.57(16H, m)

EXAMPLE 19 4-Morpholin-4-yl-6-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 332(M+1)

1H NMR: (DMSO-d6) δ 8.10-8.07(1H, t), 3.70-3.62(8H, m), 3.39-3.17(6H, m), 2.22-1.62(6H, m)

EXAMPLE 20 1-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-diethylpiperidine-3-carboxamide

MS: APCI(+ve) 374(M+1)

1H NMR: (DMSO-d6) δ 4.39(2H, m), 3.78-3.60(4H, m), 3.33-2.63(11H, m), 1.80-1.43(4H, m), 1.16-0.92(6H, m)

EXAMPLE 21 4-[4-(2-Methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 382(M+1)

1H NMR: (DMSO-d6) δ 6.99-6.87(4H, m), 3.86-3.63(15H, m), 2.99(4H, m)

EXAMPLE 22 N˜2˜-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N˜1˜,N˜1˜-bis{4-[N-4-cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N-isobutylglycyl]morpholin-3-yl}-N˜2˜-isobutylglycinamide

MS: APCI(+ve) 390(M+1)

1H NMR: (DMSO-d6) δ 4.39-4.36(2H, d), 3.62-3.31(18H, m), 2.05-1.92(1H, m), 0.87-0.85(6H, d)

EXAMPLE 23 4-Morpholin-4-yl-6-[(2-pyridin-3-ylethyl)amino]-1,3,5-triazine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 312(M+1)

1H NMR: (DMSO-d6) δ 8.69-8.64(2H, m), 8.22-8.04(2H, m), 7.78-7.70(1H, m), 3.66-3.53(10H, m), 2.97-2.93(2H, t)

EXAMPLE 24 4-{[2-(2-Furyl)ethyl]amino}-6-morpholin yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 299(M+1)

1H NMR: (DMSO-d6) δ 8.21(1H, t), 7.51(1H, s), 6.34(1H, s), 6.15(1H, s), 3.64-3.62(8H, m), 3.52-3.46(2H, m), 2.86-2.82(2H, m)

EXAMPLE 25 4-[(4-Chlorophenyl)amino]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 330(M+1)

1H NMR: (DMSO-d6) δ 10.56(1H, bs), 10.05(1H, brs), 7.66-7.40(4H, m), 3.41-3.35(8H, m), 2.81(3H, s)

EXAMPLE 26 4-Azetidin-1-yl-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 285(M−1)

1H NMR: (DMSO-d6) δ 10.32(1H, s), 7.72-7.32(4H, m), 4.15-4.10(4H, m), 2.38-2.30(2H, q)

EXAMPLE 27 4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile (i) N-(4-Chlorophenyl)-2,6-difluoropyrimidin-4-amine

4-Chloroaniline was added to a stirred solution of 2,4,6-trifluoropyrimidine (7.7 g), potassium carbonate (7.86 g) in ethanol (80 ml). The mixture was stirred at room temperature for 16 h, diluted with water, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (4:1). Yield 8.3 g cream solid

1H NMR: (DMSO-d6) δ 10.47(1H, s), 7.58(211, d), 7.45(2H, d), 6.35(1H, s)

(ii) 4-[(4-Chlorophenyl)amino]-6-fluoropyrimidine-2-carbonitrile

Sodium cyanide (0.046 g) was added to a solution of the product from step (i) (0.113 g) in dimethylsulphoxide (3 ml) and stirred at room temperature for 1.5 h. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried (MgSO4), and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (4:1). Yield 0.036 g

1H NMR: (DMSO-d6) δ 10.56(1H, s), 7.57(2H, d), 7.47(2H, d), 6.65(1H, s)

(iii) 4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

Morpholine (0.16 g) was added to a solution of the product from step (ii) (0.16 g) in iso-propylalcohol (4 ml) and stirred for 2 h at room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution, the organics separated, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (1:1). Yield 0.09 g

MS: APCI(+ve) 316(M+1)

1H NMR: (DMSO-d6) δ 9.65(1H, s), 7.52(2H, d), 7.38(2H, d), 6.08(1H, s), 3.67(4H, t), 3.48(2H, t)

EXAMPLES 28-42

Examples 28-42 were prepared according to the general method of example 27 using the appropriate amines or phenols

EXAMPLE 28 4-[(4-Methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 302(M+1)

1H NMR: (DMSO-d6) δ 7.21-7.18(1H, d), 5.83(H, s), 3.89(1H, bs), 3.88(4H, m), 3.41(4H, m), 1.63-1.28(9H, m), 0.89(3H, d)

EXAMPLE 29 4-(4-Chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(−ve) 315(M−1)

1H NMR: (DMSO-d6) δ 7.53-7.20(4H, 2×d), 6.63(1H, s), 3.65-3.63(8H, m)

EXAMPLE 30 4-[(4-Chlorophenyl)amino]-6-(dimethylamino)pyrimidine-2-carbonitrile

MS: APCI(+ve) 274(M+1)

1H NMR: (DMSO-d6) δ 9.57(1H, s), 7.55-7.34(4H, 2×d), 5.93(1H, s), 3.02(6H, m)

EXAMPLE 31 4[(1-Methylpiperidin 4-yl)amino]-morpholin-4-ylpyrimidine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 303(M+1)

1H NMR: (DMSO-d6) δ 9.36(1H, brs), 7.49-7.47(1H, d), 5.76(1H, s), 3.92(1H, bm), 3.67-3.43(8H, 2×m), 3.34-3.10(4H, m), 2.75(3H, s), 2.07-1.68(4H, m)

EXAMPLE 32 4-(Cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 288(M+1)

1H NMR: (DMSO-d6) δ 7.23-7.21(1H, d), 5.73(1H, s), 3.62-3.42(9H, m), 1.83-1.07(10H, m)

EXAMPLE 33 4[(4-Chlorophenyl)amino]-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 300(M+1)

1H NMR: (DMSO-d6) δ 9.55(1H, s), 7.54-7.35(4H, 2×d), 5.79(1H, s), 3.38(4H, m), 1.93(4H, m)

EXAMPLE 34 4-[(6-Chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(−ve) 315(M−1)

1H NMR: (DMSO-d6) δ 9.83(1H, s), 8.55-8.49(1H, s), 8.06-8.02(1H, d), 7.49-7.46(1H, d), 6.10(1H, s), 3.69-3.66(4H, m), 3.52-3.48(4H, m)

EXAMPLE 35 1-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-prolinamide

MS: APCI(+ve) 343(M+1)

1H NMR: (DMSO-d6) δ 9.33(1H, s), 7.57-7.24(4H, 2×d), 7.00(2H, bm), 5.81(1H, s), 4.31-3.38(3H, m), 2.26-1.26(4H, m)

EXAMPLE 36 4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]pyrimidine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 329(M+1)

1H NMR: (DMSO-d6) δ 9.66(1H, s), 7.88-7.36(7H, m), 6.15(1H, s), 4.23-4.20(2H, m), 3.17-2.96(3H, m), 1.98-1.38(4H, m)

EXAMPLE 37 4-[(4-Chlorophenyl)amino]-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile, acetate salt

MS: APCI(+ve) 383(M+1)

1H NMR: (DMSO-d6) δ 9.57(1H, s), 7.53-7.35(4H, 2×d), 6.09(1H, s), 4.06-2.51(9H, m), 1.92-1.90(5H, m), 1.74-1.34(6H, m)

EXAMPLE 38 4-[(4-Chlorophenyl)amino]-6-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 357(M+1)

1H NMR: (DMSO-d6) δ 9.52(2H, m), 7.63-7.36(5H, 2×d+m), 5.92(1H, bs), 3.54-2.99(8H, m), 2.00-1.84(6H, m)

EXAMPLE 39 tert-Butyl 4-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}piperazine-1-carboxylate

MS: APCI(+ve) 415(M+1)

1H NMR: (DMSO-d6) 69.66(1H, s), 7.52(2H—, d), 7.37(2H, d), 6.07(11H, s), 3.54-3.51(4H, m), 3.44-3.41(4H, m), 1.42(9H, s)

EXAMPLE 40 4-[(4-Chlorophenyl)amino]-6-(cyclopropylamino)pyrimidine-2-carbonitrile

MS: APCI(+ve) 286(M+1)

1H NMR: (DMSO-d6) δ 9.65(1H, s), 7.80(1H, s), 7.53(2H, d), 7.37(2H, d), 6.08(1H, s), 0.76-0.71(2H, m), 0.50-0.46(2H, m)

EXAMPLE 41 4-[(4-Chlorophenyl)amino]-6-piperazin-1-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 315(M+1)

1H NMR: (DMSO-d6) δ 9.62(1H, s), 7.53(2H, d), 7.37(2H, d), 6.07(1H, s), 3.46(4H, t), 2.79(4H, t)

EXAMPLE 42 (2S)-N˜2˜-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-N˜1˜,N˜1˜-bis[4-(N-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-leucyl)morpholin-3-yl]-L-leucinamide

MS: APCI(+ve) 429(M+1)

1H NMR: (DMSO-d6) δ 9.51(1H, s), 7.82(1H, d), 7.46(2H, d), 7.37(2H, d), 6.09(1H, s), 4.87(1H, s), 3.67-3.47(6H, m), 3.35-3.25(2H, m), 1.66-1.53(2H, m), 1.48-1.39(1H, m), 0.92-0.89(6H, m)

EXAMPLE 43 5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile (i) 4-(5-Chloro-2,6-difluoropyrimidin-4-yl)morpholine

Morpholine (0.774 mg) was added to a solution of 5-chloro-2,4,6-trifluoropyrimidine (1.5 g), N,N-diisopropylethylamine (1.15 g) in 1,4-dioxane (30 ml) and stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water, the organic layer dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 8% ethyl acetate in isohexane. Yield 0.88 g

(ii) 5-Chloro-N-(4-chlorophenyl)-2-fluoro-6-morpholin-4-ylpyrimidin-4-amine

4-Chloroaniline (1.44 g) was added to a solution of the product from step (i) (0.88 g) and N,N-diisopropylethylamine (0.484 g) in 1,4-dioxane (15 ml) and isopropylalcohol (15 ml) and the mixture heated at 110° C. for 6 days. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4), and evaporated under reduced pressure. The solid was triturated with ethyl acetate, filtered and the filtrate purified by chromatography on silica eluting with 3% ethyl acetate in toluene. Yield 0.28 g

MS: APCI(+ve) 343/5(M+1)

(iii) 5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

Sodium cyanide (0.057 g) was added to a solution of the product from step (ii) (0.2 g) in dimethylsulphoxide (5 ml) and the mixture stirred at room temperature. After 18 h, the mixture was partitioned between ethyl acetate and water, the organics separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in toluene. Yield 0.09 g

MS: APCI(−ve) 348(M−1)

1H NMR: (DMSO-d6) δ 9.34(1H, s), 7.53(2H, d), 7.42(2H, d), 3.71(4H, t), 3.55(4H, t)

EXAMPLE 44 4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile, trifluoroacetate salt (i) 5-Methoxy-2-thioxodihydropyrimidine-4,6(1H,5H)-dione

Thiourea (24 g) and methoxymethyl malonate (34 g) was added to a solution of sodium (12 g) in methanol and the mixture heated under reflux for 10 h. The methanol was evaporated under reduced pressure, water (500 ml) added and extracted with ether. The aqueous layer was acidified to pH1 with conc. hydrochloric acid, evaporated to ˜200 ml and the precipitate filtered and dried. Yield 23 g

1H NMR: (DMSO-d6) δ 11.31(2H, s), 3.48(3H, s)

(ii) 2-(Ethylthio)-5-methoxypyrimidine-4,6(1H,5H)-dione

Ethyl iodide (11.2 ml) was added dropwise to a stirred mixture of the product from step (i) (23 g) and sodium hydroxide (6 g) in water (400 ml). After 16 h the mixture was filtered, the filtrate acidified to pH1 and the precipitate filtered, washed with water and dried. Yield 17.8 g

1H NMR: (DMSO-d6) δ 12.25(1H, s), 3.59(3H, s), 3.57(1H, s), 3.06(2H, q), 1.28(3H, t)

(iii) 4,6-Dichloro-2-(ethylthio)-5-methoxypyrimidine

A mixture of the product from step (ii) (17.8 g) and N,N-diethylaniline (20 ml) in phosphorus oxychloride (400 ml) was heated at 100° C. for 3 h. The excess reagent was removed under reduced pressure and the residue poured onto ice and extracted with ether. The ether layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in isohexane. Yield 12.8 g

(iv) 6-Chloro-N-(4-chlorophenyl)-2-(ethylthio)-5-methoxypyrimidin-4-amine

A solution of the product from step (iii) (4 g) and 4-chloroaniline (5.3 g) in ethanol (40 ml) was heated under reflux for 16 h then the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and 2M hydrochloric acid, the organics washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10-15% ethyl acetate in isohexane. Yield 4.99 g

MS: APCI(+ve) 330/2(M+1)

(v) 4-Chloro-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile

A mixture of the product from step (iv) (4.9 g) and 3-chloroperoxybenzoic acid (10 g, Aldrich 77% max.) in dichloromethane (150 ml) was stirred at room temperature for 3 h, washed with aqueous sodium metabisulphite solution, water, aqueous sodium hydrogencarbonate solution, water, dried (MgSO4) and evaporated under reduced pressure. The solid was dissolved in dimethylsulphoxide (40 ml), sodium cyanide (1.1 g) added and stirred for 2 h at room temperature. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30% ethyl acetate in isohexane.

Yield 3.23 g

MS: APCI(+ve) 295/7(M+1)

(vi) 4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile

A solution of the product from step (v) (0.25 g) and piperazine (0.366 g) in tetrahydrofuran (8 ml) was heated at 60° C. for 6 h then the solvent removed under reduced pressure. The residue was purified by RPHPLC 15-75% acetonitrile in aqueous trifluoroacetic acid.

Yield 0.139 g

MS: APCI(+ve) 345(M+1)

1H NMR: (DMSO-d6) δ 9.29(1H, s), 8.92(2H, s), 7.67(2H, d), 7.40(2H, d), 3.83-3.80(4H, m), 3.69(3H, s), 3.25-3.23(4H, m)

Mpt 230° C.

EXAMPLES 45-51

Examples 45-51 were prepared according to the method of example 44 using the appropriate amines

EXAMPLE 45 4-[(4-Chlorophenyl)amino]-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 346(M+1)

1H NMR: (DMSO-d6) δ 9.20(1H, s), 7.67(2H, d), 7.38(2H, d), 3.73-3.70(4H, m), 3.68(3H, s), 3.63-3.61(4H, m)

Mpt 176° C.

EXAMPLE 46 4-[(3S)-3-Aminopyrrolidin-1-yl]-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 345/7(M+1)

1H NMR: (DMSO-d6) δ 9.12(1H, s), 8.10(3H, s), 7.66(2H, d), 7.38(2H, d), 3.91-3.69(5H, m), 3.65(3H, s), 2.33-2.22(1H, m), 2.08-2.01(1H, m)

Mpt 345-7° C.

EXAMPLE 47 4-[(4-Chlorophenyl)amino]-6-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-5-methoxypyrimidine-2-carbonitrile, bis-trifluoroacetate salt

MS: APCI(+ve) 430/2(M+1)

1H NMR: (DMSO-d6) 90° C. δ 8.94(11, s), 7.64(2H, d), 7.35(2H, d), 3.81(4H, brs), 3.70(3H, s), 3.15-3.09(2H, m), 3.00(4H, brs), 2.86(2H, brs), 2.81(6H, s), 2.03-1.95(2H, m)

Mpt 210-2° C.

EXAMPLE 48 4-[(4-Chlorophenyl)amino]-6-(dimethylamino)₅-methoxypyrimidine-2-carbonitrile

MS: APCI(−ve) 302/4(M−1)

1H NMR: (DMSO-d6) 90° C. δ 9.08(1H, s), 7.66(2H, d), 7.37(2H, d), 3.62(3H, s), 3.13(6H, s)

Mpt 173° C.

EXAMPLE 49 4-[(4-Chlorophenyl)amino]-5-methoxy-6(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile

MS: APCI(−ve) 357/9(M−1)

1H NMR: (DMSO-d6) δ 9.24(1H, s), 8.10(1H, s), 7.67(2H, d), 7.39(2H, d), 4.17(2H, s), 3.85-3.83(2H, m), 3.66(3H, s), 3.32-3.29(2H, m)

Mpt 244° C.

EXAMPLE 50 1-{6-[(4-Chlorophenyl)amino]-2-cyano-5-methoxypyrimidin-4-yl}piperidine-3-carboxamide

MS: APCI(+ve) 387/9 (M+1)

1H NMR: (DMSO-d6) δ 9.16(1H, s), 7.68(2H, d), 7.40-7.35(3H, m), 6.89(1H, s), 4.34-4.25(2H, m), 3.65(3H, s), 3.07-2.92(2H, m), 2.35-2.40(1H, m), 1.90-1.51(4H, m)

EXAMPLE 51 4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile, trifluoroacetate salt

MS: APCI(+ve) 359/61 (M+1)

1H NMR: (DMSO-d6) δ 9.20(1H, s), 7.93(3H, s), 7.67(2H, d), 7.39(2H, d), 4.36-4.32(2H, m), 3.66(3H, s), 3.08-3.01(2H, m), 2.00-1.97(2H, m), 1.57-1.54(2H, m)

EXAMPLE 52 5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile (i) N-(4-Chlorophenyl)-6-morpholin-4-yl-5-nitro-2-(propylthio)pyrimidin-4-amine

Morpholine (1.31 ml) was added dropwise to a stirred solution of 4,6-dichloro-5-nitro-2-thiopropyl pyrimidine (4 g), N,N-diisopropylamine (7 ml) in dichloromethane (50 ml) at 0° C. After 1 h, 4-chloroaniline (1.9 g) was added, the mixture stirred at room temperature for 24 h, then heated under reflux for 24 h. The mixture was partitioned between dichloromethane and 2M hydrochloric acid, the organics washed with water, dried (MgSO4) and evaporated under reduced pressure. Yield 5 g

MS: APCI(+ve) 410/2 (M+1)

(ii) 4-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-5-nitropyrimidine-2-carbonitrile

A mixture of the product from step (i) (5 g) and 3-chloroperoxybenzoic acid (12 g, Aldrich 77% max.) in dichloromethane (200 ml) was stirred at room temperature for 2 h, washed with aqueous sodium metabisulphite solution, water, aqueous sodium hydrogencarbonate solution, water, dried (MgSO4) and evaporated under reduced pressure. The solid was dissolved in dimethylsulphoxide (30 ml), sodium cyanide (2 g) added and stirred for 1 h at room temperature. Water (500 ml) was added and the solid filtered, washed with water, dried and the residue triturated with ether. Yield 1.7 g

MS: APCI(+ve) 361/3 (M+1)

(iii) 5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

The product from step (ii) (1.7 g) and 10% palladium on charcoal (0.2 g) in ethyl acetate (300 ml) was hydrogenated at 2 Bar for 8 h, filtered through celite and the solvent evaporated under reduced pressure. Yield 1.05 g

MS: APCI(+ve) 329/331 (M+1)

1H NMR: (DMSO-d6) δ 8.66(1H, s), 7.62(2H, d), 7.39(2H, d), 5.53(2H, s), 3.78-3.76(4H, m), 3.08-3.06(4H, m)

Mpt 253-4° C.

EXAMPLE 53 5-Amino-4[(4-Chlorophenyl)amino]-6(ethylamino)pyrimidine-2-carbonitrile

Example 53 was prepared according to the general method of example 52 using the appropriate amine

MS: APCI(+ve) 289/91(M+1)

1H NMR: (DMSO-d6) δ 8.19(1H, s), 7.50(2H, d), 7.31(2H, d), 6.52(1H, t), 5.20(2H, s), 3.41-3.35(2H, m), 1.18(3H, t)

Mpt 211-2° C.

Measurement of Cathepsin S Activity.

QFRET Technology (Quenched Fluorescent Resonance Energy Transfer) was used to measure the inhibition by test compounds of Cathepsin S-mediated cleavage of the synthetic peptide Z-Val-Val-Arg-AMC. Compounds were screened at five concentrations in duplicate and the pIC₅₀ values reported.

Synthetic substrate, 20 μM [final]Z-Val-Val-Arg-AMC in phosphate buffer were added to a 96 well black Optiplate. The assay plates were pre-read for compound auto fluorescence on SpectraMax Gemini at 355 nM excitation and 460 nM emission. 250 pM [final] rHuman Cathepsin S in phosphate buffer was added and incubated for 2 h at room temperature on the SpectraMax Gemini, taking readings every 20 min at 355 nM excitation and 460 nM emission.

Activity Based template (5PTB-8) used the auto fluorescent corrected data to calculate the percentage inhibition for each compound concentration using the relevent plate controls. This data was used to construct inhibition curves and pIC₅₀ estimated by non-linear regression using a 4 parameter logistic model. 

1. A method of inhibiting cathepsin S in a mammal comprising administering a compound of formula (I) to said mammal

in which: X is N or CA where A is hydrogen, halogen, CHR²R³, OR², NR²R³, SR; R² and R³ are independently hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl both of which can optionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl, and can be optionally substituted by aryl, heteroaryl, NR⁵R⁶ where R and R⁶ together with the nitrogen atom to which they are attached form a 4-7 membered ring optionally containing a further O, S, NR⁴, or R2 and R3 together with the nitrogen atom to which they are attached form a 4-7 membered ring optionally containing a further O, S, NR⁴ group, or R2 and R3 are aryl or heteroaryl groups, both aryl and heteroaryl groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, NR⁷R⁸ or SR⁷ where R⁷ and R⁸ are independently hydrogen or C₁₋₆ alkyl; R and R¹ are independently a group Y(CH₂)pR⁹ where p is 0, 1, 2 or 3 and Y is O or NR¹⁰ where R¹⁰ is hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and R⁹ is hydrogen, C₁₋₆ alkyl which can optionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl, or a 3 to 7-membered saturated ring optionally containing a carbonyl group, one or more O, S or N atoms, or an aryl or heteroaryl group containing one to four heteroatoms selected from O, S or N, the saturated ring, aryl and heteroaryl groups all being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or NR¹¹R¹² where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR⁴ group; or R/R¹ is a group NR¹⁰(CHR¹⁰)CONR²R³ or NR¹⁰(CH₂)_(q)CONR²R³ where q is 1, 2 or 3; or R/R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated ring optionally containing a carbonyl group, O, S or N atom and optionally substituted by C₁₋₆ alkyl, amino, hydroxy, CO₂C₁₋₆ alkyl, halogen, NR⁵R⁶, NR⁷R⁸, C₁₋₆ alkylNR¹⁷R¹⁸ where R¹⁷ and R¹⁸ are independently hydrogen or C₁₋₆ alkyl, CONR¹⁵R¹⁶ where R¹⁵ and R¹⁶ are independently hydrogen or C₁₋₆ alkyl, or optionally substituted by aryl, phenoxy, COphenyl, or a heteroaryl group, the latter four groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or NR¹¹R¹² where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR⁴ group; and pharmaceutically acceptable salts or solvates thereof, in the manufacture of a medicament for use in the inhibition of cathepsin S in a mammal such as man.
 2. The method according to claim 1 in which X is CH, NHR², OR² wherein R² is hydrogen or C₁₋₆ alkyl.
 3. The method according to claim 1 in which R is a group Y(CH₂)pR⁷ where p is 0 or 1 and Y is NR⁸ wherein R⁸ is hydrogen and R⁷ is substituted phenyl.
 4. The method according to claims 1 in which R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form a morpholine ring, piperidine or piperazine ring optionally substituted.
 5. The method according to claim 1 in which R¹ is a group NR⁹R¹⁰ where R¹⁰ is H or C₁₋₆ alkyl and R⁹ is C₁₋₆ alkyl which can optionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl.
 6. The method according to claim 1 where the compound of formula (I) is selected from: 4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile, 4-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, 4-(7-Azabicyclo[2.2.1]hept-7-yl)-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-piperidin-1-yl-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-(ethylamino)-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-(3-hydroxypyrrolidin-1-yl)-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-[(2-piperidin-1-ylethyl)amino]-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile, 4-[(3-Chlorobenzyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile, 4-Morpholin-4-yl-6-[(4-morpholin-4-ylphenyl)amino]-1,3,5-triazine-2-carbonitrile, 4-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, 4-Morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile, 4-(1,4′-Bipiperidin-1′-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, 4-[4-(1H-Imidazol-1-yl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, 4-[4-(4-Chlorobenzoyl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, 4-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, 4-Morpholin-4-yl-6-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3,5-triazine-2-carbonitrile, 1-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-diethylpiperidine-3-carboxamide, 4-[4-(2-Methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, N˜2˜-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N˜1˜,N˜1˜-bis{4-[N-(4-cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N-isobutylglycyl]morpholin-3-yl}-N˜2˜-isobutylglycinamide, 4-Morpholin-4-yl-6-[(2-pyridin-3-ylethyl)amino]-1,3,5-triazine-2-carbonitrile, 4-{[2-(2-Furyl)ethyl]amino}-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-carbonitrile, 4-Azetidin-1-yl-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, 4-[(4-Methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, 4-(4-Chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-(dimethylamino)pyrimidine-2-carbonitrile, 4-[(1-Methylpiperidin-4-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, 4-(Cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile, 4-[(6-Chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, 1-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-prolinamide, 4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]pyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidine-2-carbonitrile, tert-Butyl 4-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}piperazine-1-carboxylate, 4-[(4-Chlorophenyl)amino]-6-(cyclopropylamino)pyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-piperazin-1-ylpyrimidine-2-carbonitrile, (2S)-N˜2˜-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-N˜1˜,N˜1˜-bis[4-(N-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-leucyl)morpholin-3-yl]-L-leucinamide, 5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile, 4-[(3S)-3-Aminopyrrolidin-1-yl]-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-5-methoxypyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-5-methoxypyrimidine-2-carbonitrile, 4-[(4-Chlorophenyl)amino]-5-methoxy-6-(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile, 1-{6-[(4-Chlorophenyl)amino]-2-cyano-5-methoxypyrimidin-4-yl}piperidine-3-carboxamide, 4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile, 5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile, 5-Amino-4-[(4-Chlorophenyl)amino]-6-(ethylamino)pyrimidine-2-carbonitrile, and pharmaceutically acceptable salts thereof.
 7. A compound of formula (I):

in which: X is CA where A is hydrogen, halogen, CHR²R³, OR², NR²R³, SR²; R² and R³ are independently hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl both of which can optionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl, and can be optionally substituted by aryl, heteroaryl, NR⁵R⁶ where R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 4-7 membered ring optionally containing a further O, S, NR⁴, or R2 and R3 together with the nitrogen atom to which they are attached form a 4-7 membered ring optionally containing a further O, S, NR⁴ group, or R2 and R3 are aryl or heteroaryl groups, both aryl and heteroaryl groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, NR⁷R⁸ or SR⁷ where R⁷ and R⁸ are independently hydrogen or C₁₋₆ alkyl; R and R¹ are independently a group Y(CH₂)pR⁹ where p is 0, 1, 2 or 3 and Y is O or NR¹⁰ where R¹⁰ is hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and R⁹ is hydrogen, C₁₋₆ alkyl which can optionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl, or a 3 to 7-membered saturated ring optionally containing a carbonyl group, one or more O, S or N atoms, or an aryl or heteroaryl group containing one to four heteroatoms selected from O, S or N, the saturated ring, aryl and heteroaryl groups all being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or NR¹¹R¹² where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR⁴ group; or R/R¹ is a group NR¹⁰(CHR¹⁰)CONR²R³ or NR¹⁰(CH₂)_(q)CONR²R³ where q is 1, 2 or 3; or R/R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated ring optionally containing a carbonyl group, O, S or N atom and optionally substituted by C₁₋₆ alkyl, amino, hydroxy, CO₂C₁₋₆ alkyl, halogen, NR⁵R⁶, NR⁷R⁸, C₁₋₆ alkylNR¹⁷R¹⁸ where R¹⁷ and R¹⁸ are independently hydrogen or C₁₋₆ alkyl, CONR¹⁵R¹⁶ where R¹⁵ and R¹⁶ are independently hydrogen or C₁₋₆ alkyl, or optionally substituted by aryl, phenoxy, COphenyl, or a heteroaryl group, the latter four groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or NR¹¹R¹² where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR⁴ group; or pharmaceutically acceptable salts or solvates thereof.
 8. (canceled)
 9. A pharmaceutical composition which comprises a compound of the formula (I) as defined in claim 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
 10. A method for producing inhibition of a cysteine protease in a mammal, such as man, in need of such treatment, which comprises administering to said mammal an effective amount of a compound of the present invention as defined in claim 7 or a pharmaceutically acceptable salt thereof. 